Copper-Catalyzed Synthesis of Substituted Quinazolines from

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Copper-Catalyzed Synthesis of Substituted Quinazolines from Benzonitriles and 2-Ethynylanilines via CarbonCarbon Bond Cleavage Using Molecular Oxygen Xu Wang, Dandan He, Yubing Huang, Qihang Fan, Wanqing Wu, and Huanfeng Jiang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00378 • Publication Date (Web): 24 Apr 2018 Downloaded from http://pubs.acs.org on April 24, 2018

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The Journal of Organic Chemistry

Copper-Catalyzed Synthesis of Substituted Quinazolines from Benzonitriles and 2-Ethynylanilines via Carbon-Carbon Bond Cleavage Using Molecular Oxygen Xu Wang,b Dandan He,b Yubing Huang,b Qihang Fan,b Wanqing Wu*,a,b, Huanfeng Jiang*,b a.

State Key Laboratory of Luminescent Materials and Devices, South China University of Technology, Guangzhou

510640, China b.

Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and

Chemical Engineering, South China University of Technology, Guangzhou 510640, China Fax: (+86) 20-87112906; E-mail: [email protected], [email protected]

Abstract: A copper-catalyzed process for the synthesis of substituted quinazolines from benzonitriles and 2-ethynylanilines using molecular oxygen (O2) as sole oxidant is described. The mild catalytic system enabled the effective cleavage of the C-C triple bond and construction of new C−N, C−C bonds in one operation. Furthermore, the compound N,N-dimethyl-4-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)aniline (3dj) exhibited obvious aggregation-induced emission (AIE) phenomenon, and the fluorescence quantum yield (ΦF,film) and lifetime (τfilm) were measured to be 45.5% and 5.8 ns in thin films state, respectively.

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INTRODUCTION Transition metal-catalyzed carbon-carbon bond cleavage has been recognized as a challenging and attractive area, which provides a new chemical reaction model for organic synthesis.1 Over the past several decades, much progress has been achieved in the cleavage of carbon-carbon single bonds and carbon-carbon double bonds.2,3 However, only a few examples on carbon-carbon triple bond cleavage reactions have been reported, which is due to its extraordinarily large bond dissociation energy (>200 kcal/mol) required.2a In order to achieve this goal,2a,3a,3d many noble metal catalysts and stoichiometric amount of nonrenewable oxidants are often employed to activate carbon-carbon triple bond, thereby making their application less desirable. Thus, there is still room for broadening the scope of more environmentally friendly and more economic “green” methods to activate carbon-carbon triple bond. Scheme 1. Transformations of 2-Alkynylanilines and Indoles

N-Heterocyclic compounds play an important role in organic synthesis because of their abundance in numerous natural products, biologically active compounds and materials.4 2-Alkynylanilines as highly versatile building blocks has proven wide


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application in the construction of N-heterocyclic compounds.5 In the past decades, transition-metal-catalyzed intramolecular cyclization of 2-ethynylanilines have attracted great attention as one of the efficient strategies to assemble substituted indoles.6-14 Most of these strategies involved the intramolecular aminometalation to afford 3-indoly-metal species, which is trapped with suitable electrophiles or oxidative coupling with nucleophiles (Scheme 1a). Although much progress has been achieved in this area, the exploration of novel catalytic system to enrich the diversity of the transformation remains an active research field. Recently, Song and Wang’s group developed the palladium-catalyzed addition of indoles with nitriles through 3-indoly-palladium intermediates. which provides a valid path to 3-acylindoles (Scheme 1b).15 Nevertheless, the nitrogen atoms of nitriles have not been effectively utilized owing to the hydrolysis of ketimine intermediates. Based on our continuous interest in the effective transformation of nitriles,16 we describe a copper-catalyzed synthesis of substituted quinazolines17 from benzonitriles and 2-ethynylanilines via carbon-carbon triple bond cleavage using molecular oxygen (O2) as sole oxidant. This strategy enables effective assembly of quinazolines by C-N, C-C bond formations and aerobic C-C triple bond cleavage (Scheme 1c). RESULTS AND DISCUSSION In preliminary experiments, 2-(phenylethynyl)aniline (1a, 0.2 mmol) was treated with Cu(OAc)2 (10 mol %), t-BuOK (3 equiv), and benzonitrile (2a, 0.3 mmol) in DMSO (2 mL) under 1 atm O2 atmosphere at 120 oC for 24 h, and the desired product 2,4-diphenylquinazoline (3aa) was observed in 62% yield (Table 1, entry 1). Then, a



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series of copper catalysts were screened and did not display better catalytic activity than Cu(OAc)2 (Table 1, entries 2-5). The examination of bases revealed that t-BuOK was the most suitable base for this reaction system (Table 1, entries 6-12). Other bases presumably are not conducive to the formation of intermediate A (see Scheme 4), and the intramolecular cyclization product 2-phenyl-1H-indole was obtained in these cases. However, the use of DMA, DMF, dioxane, toluene or acetonitrile as solvent was proven to be disadvantageous to the reaction, as the yields were significantly decreased

(Table

1,

entries

13-17).

Surprisingly,

the

reaction

of

2-(phenylethynyl)aniline (1a) with benzonitrile (2a) gave the 2-phenylquinazoline product (4aa) in 67% yield when toluene was used as the solvent. Reducing the amount of solvent to 0.5 mL resulted in a higher yield (Table 1, entries 1 vs. 18). Notably, when the initial substrate ratio was changed, the yield of 3aa enhanced from 81% to 87% (Table 1, entries 18 vs. 19). It is remarkable that the yield decreased significantly by using anhydrous DMSO as the solvent (Table 1, entry 20). The importance of H2O was further proven by adding H2O (5.0 equiv) to anhydrous DMSO, which gave an improved yield of 3aa (Table 1, entries 20 vs. 21). Hence, 1a (0.2 mmol), 2a (0.4 mmol), Cu(OAc)2 (10 mol %), t-BuOK (3 equiv) in DMSO (0.5 mL) under 1 atm O2 atmosphere at 120 oC for 24 h were chosen as the optimized conditions. Table 1. Optimization of Reaction Conditionsa


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Entry

Catalyst

Base

Solvent

Yield 3aa/4aa (%)b

1 2 3

Cu(OAc)2 Cu(OTf)2

t-BuOK t-BuOK t-BuOK

DMSO DMSO DMSO

62/0 trace/0

t-BuOK

DMSO

trace/0

t-BuOK K2CO3

DMSO DMSO DMSO

4

a

CuSCN

5 6 7

CuCl2 CuBr2 Cu(OAc)2 Cu(OAc)2

8 9 10

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

11 12 13 14 15c 16c 17c 18d 19e 20e,f 21e,g

trace/0

Cu(OAc)2

NEt3 t-BuONa

DMSO

trace/0 0/0 0/0 0/0 0/0 0/0 trace/0

Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2

t-BuOLi t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK

DMSO DMA DMF dioxane toluene acetonitrile DMSO DMSO DMSO DMSO

trace/0 24/0 27/0 0/0 19/67 0/0 81/0 87/0 51/0 84/0

Cs2CO3 NaCO3 Ag2CO3

DMSO DMSO DMSO

All reactions were carried out under the following conditions: 1a (0.2 mmol), 2a (0.3 mmol),

catalyst (10 mol %), base (3 equiv), solvents (2 mL), 120 oC, 24 h, with an O2 balloon. bGC yield using dodecane as internal standard. Yields determined by GC based on 1a with n-dodecane as internal standard. c100 oC. dSolvents (0.5 mL). e1a (0.2 mmol), 2a (0.4 mmol), solvents (0.5 mL). f

Anhydrous DMSO with 100 mg of 4 Å MS. gAnhydrous DMSO with addition of H2O (5.0 equiv).

To explore the scope and limitations of this approach, various aryl substituted nitriles 2b-2o were applied to the reaction with 2-(phenylethynyl)aniline (1a) under the optimized conditions. Typical results are shown in Table 2. To our delight, most of the reactions proceeded smoothly to afford the corresponding quinazoline products in moderate to good yields (3aa-3am). The crystallization of compound 3aa from



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anhydrous ethanol gave single crystals suitable for X-ray analysis. The benzonitriles 2b-2f possessing electron-donating group, such as 4-methyl, 2-methyl, 4-isopropyl, 4-methoxy and 1,3-methylenedioxy at the aryl ring could transfer to the desired products

3ab-3af

in

electron-withdrawing

41%-62% group,

yields,

including

and

some

4-chloro,

substrates

2-chloro,

bearing

4-bromo

an and

4-trifluoromethyl at the benzene ring also reacted smoothly and afforded the desired products 3ag-3aj in 67-88% yields. Obviously, the electron-deficient aryl substituted nitriles performed better than the electron-rich aryl substituted ones. This might be due to the electron-rich benzonitriles are unfavorable for the nucleophilic addition of the amino group (see the proposed mechanism in Scheme 4). Sterically hindered substrates such as 1- and 2-naphthonitrile also transformed to the expected products 3al and 3ak in 64% and 51% yields. Furthermore, nitriles bearing a heterocyclic substituent such as 2-furonitrile and 2-thiophene could also convert to the desired products 3am and 3bp in moderate yields. In addition, the transformation of 2-(phenylethynyl)aniline (1b) possessing an electron-withdrawing group at the aryl ring (R2 = 4-ClC6H4) afforded the desired products 3bn and 3bo in 57% and 56% yields. The transformations of substrates 1c and 1d possessing an electron-donating group (R2 = 4-MeC6H4 and R2 = 4-(dimethylamino)-C6H4) at the benzene ring also gave the corresponding products 3cm and 3dj in 41% and 46% yields. The intramolecular cyclization side product 2-phenyl-1H-indoles 5c and 5d were detected in

45%

and

39%

GC

yields

in

these

cases.

The

electron-donating

5-methoxy-substituted (1j) and the electron-withdrawing 4-chloro-substituted (1k)


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2-ethynylanilines were both reacted with 2a under the optimal conditions to provide 3ja and 3ka in 57% and 49% yields. Table 2. Synthesis of Substituted Quinazolines 3a,b

a

All reactions were carried out under the following conditions: 1 (0.2 mmol), 2 (0.4 mmol),

Cu(OAc)2 (10 mol %), t-BuOK (3 equiv) and DMSO (0.5 mL), 120 oC, 24 h with an O2 balloon. b

Isolated yields.

Next, we investigated the effects of different 2-(phenylethynyl)anilines on the synthesis of 2-phenylquinazoline (4aa) (Scheme 2). Further research showed that the 2-(phenylethynyl)anilines bearing an electron-donating substituent (1e and 1f) produced a higher yield of product 4aa than those analogues bearing an electron-withdrawing substituent (1b and 1f). No desired product was detected when



heterocyclic-substituted alkyne was used (1g). Scheme 2. Screening for the Alkynesa,b

a

Reaction conditions: 1 (0.2 mmol), 2a (0.3 mmol), Cu(OAc)2 (10 mol %), t-BuOK (3.0 equiv),

toluene (0.5 mL), 100 oC, 12 h, with an O2 balloon. bGC yield using n-dodecane as internal standard. Yields determined by GC based on 1 with n-dodecane as internal standard. Isolated yield is in the parentheses.

Later, we turned our attention to the scope of this transformation. The scope of aromatic nitriles and substituted 2-alkynylanilines were investigated under the optimal conditions (Table 3). It was found that benzonitriles with various functional groups were successfully transformed to the desired 2-(phenylethynyl)anilines in moderate to good yields (4eb-4in). In general, the reaction yield was comparatively higher when electron-withdrawing group (i.e.−F, −Cl, −Br and −CF3) was present on the benzene ring. This result could be explained by electron-deficient benzonitriles benefit from the nucleophilic addition of the amino group. Furthermore, nitriles bearing a heterocyclic substituent such as 2-furonitrile also gave the desired product in 54% yield (4em), and amides were found as side products in these reactions. Table 3. Synthesis of Substituted Quinazolines 4a,b


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O Cu(OAc)2 (10 mol %) t-BuOK (3 equiv) R1

+

R3

N

NH2 2

1

N

R1

toluene (0.5 mL) 100 oC, 12 h O2 balloon

N

N

N

N

N

N

N

R3

4

Cl

F

N

N

F

Br 4ej, 87%

N N 4hj, 76%

a

N

N

N 4ei, 72%

4eg, 82%

4eq, 79%

4eb, 71%

F

F

4em 54%

N

N F

N

O

N

Br

N

F 4hn, 72%

F

4in, 69%

All reactions were carried out under the following conditions: 1 (0.2 mmol), 2 (0.3 mmol),

Cu(OAc)2 (10 mol %), t-BuOK (3 equiv) and toluene (0.5 mL), 100 oC, 12 h, with an O2 balloon. b

Isolated yields.

A series of control experiments were subsequently carried out to develop a deeper understanding of the reaction mechanism (Scheme 3). We conducted the radical scavengers such as TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) or BHT (3,5-di-tert-butyl-4-hydroxytoluene) to the reaction system (Scheme 3a). In both cases, the formation of 3aa was affected dramatically on the whole. The reaction of 2-(phenylethynyl)aniline (1a) with benzonitrile (2a) was carried out under a nitrogen atmosphere, and the corresponding 2,4-diphenylquinazoline (3aa) was not obtained, with 2-phenyl-1H-indole (5a) as the major product (Scheme 3b), which indicated that the reaction required the presence of oxygen. The compound 1a was subjected to the optimized reaction conditions in DMSO and gave 6a and 5a in 67% and 27% yields, respectively. When toluene was used as the solvent in the reaction, the product 6a was



formed in 92% yield (Scheme 3c). When 6a was treated with 2a, the desired product 3aa was obtained in 92% yield (Scheme 3d), which suggested that 6a should be the possible intermediate under the standard reaction conditions. Additionally, when 5a was subjected to the optimized reaction conditions, 6a could be isolated in 51% yield (Scheme 3e). However, the reaction of 5a and 2a was conducted under the standard conditions, only trace amount of products 6a and 3aa could be detected (Scheme 3f), and 5a presumably is not conducive to the formation of intermediate A due to the coordination of copper and nitrile (see Scheme 4). These results demonstrated that 5a might not be the intermediate in the current reaction system. Scheme 3. Control Experiments


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On the basis of the above results and previous reports,18 we proposed a plausible reaction mechanism for this transformation detailed in Scheme 4. This transformation pathway is initiated by aminocupration of 2-alkynyl aniline to afford the organocopper(II) intermediate A, which would be further oxidized to intermediate B in the presence of oxygen. Then, the intramolecular nucleophilic addition of peroxy anion to the C-N double bond forms a four-membered ring C. Cracking of the peroxy bond gives the intermediate D, which undergoes the [1,3]-H shift and protonated to form the intermediate E ([M+Na]+= 348.0683). Subsequently, intermediate F is formed by C-N bond cleavage. In path I, intermediate F with OH- adduct affords intermediate G, which undergoes rearrangement/decarboxylation to yield intermediate I, followed by collapse to release 6a. Finally, the condensation of 6a with benzonitrile 2a gives 3aa. When toluene is used as solvent (path II), the nitrile group can be readily activated through the coordination with the potassium cation in the presence of t-BuOK.18d The addition of the amino group of F to nitrile group generates the intermediate J. Then the intramolecular cyclization of J affords K ([M+Na]+= 333.0996), which quickly converts into intermediate L by OH- addition. Eventually, L undergoes cleavage to yield hydroxide ion, benzoic acid ([M+Na]+= 145.0258 ), and 4aa.18e,18f Scheme 4. Possible Reaction Mechanism



Interestingly, only 3dj of all the products shows bright emission in the solid state, when excited under an ultraviolet lamp (365 nm), and the fluorescence quantum yield (ΦF,film) and lifetime (τfilm) were measured to be 45.5% and 5.8 ns in thin films state, respectively. Furthermore, the fluorescence spectra of 3dj exhibited obvious wavelength changes in different solvents, which showed that the Stokes shift increased quickly on increasing the solvent polarity (Figures 1a and 1b). In order to evaluate the optical properties of product 3dj, the PL spectra of 3dj in the THF/water mixtures with various water content was then investigated (Figure 1c). In pure THF solution, 3dj exhibits bright green luminescence, however, the photoluminescence intensity showed nearly sustained decrease until the water fraction (fw) reached 70%, and the 41nm red shift could also be detected. This phenomenon could be attributed to an increase in the solvent polarity and intramolecular charge-transfer (ICT) mechanism. From 73% fw to 90% fw, the PL intensity of 3dj gradually increased,


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demonstrating the aggregation induced emission (AIE) effect. In this stage, because increasing the water content would reduce the solubility, 3dj began to aggregate. Meanwhile, the ICT effect was efficiently weakened. The fluorescence intensity of 3dj in water/THF mixture (fw = 90%) buffered by BR under different pH conditions was also determined (Figure 1d). A weak fluorescence intensity was seen at pH 1. With the gradually increase of the pH from 2 to 5, enhanced fluorescence intensity was observed. When adjusted the pH of the solution from 6 to 12, the emission behavior was similar, indicating that no state change at the range pH values, and the fluorescence intensity at 482 nm was plotted at different pH values (on the Figure 1d).

Figure 1. (a) Excitation spectra of 3dj in different solvents. (b) Emission spectra of 3dj in different solvents. (c) Fluorescence spectra of 3dj in THF/water mixtures (10-5 mol/L). (d) Fluorescence spectra of 3dj in solutions (10-5 mol /L) of different pH.



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CONCLUSION In conclusion, we have developed a concise construction of substituted quinazoline derivatives

via

Cu(OAc)2-catalyzed

cyclization

of

2-ethynylanilines

with

benzonitriles. The process produced substituted quinazolines in moderate to good yields with readily available staring materials and catalyst. With this powerful synthetic strategy, we discovered a new solid-state blue-emitting organic molecule. This method provided a clue about the further development of new types of aggregation induced emission (AIE) luminescent materials.

EXPERIMENTAL SECTION General Information: NMR spectra were obtained using a Bruker Avance 400 spectrometer (1H at 400 MHz, and

13

C at 101 MHz). Chemical shifts for 1H NMR

spectra are reported in parts per million (ppm) from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: δ 7.26 ppm). Chemical shifts for 13C NMR spectra are reported in parts per million (ppm) from tetramethylsilane with the solvent as the internal standard (CDCl3: δ 77.0 ppm). IR spectra were obtained either as potassium bromide pellets or as liquid ﬁlms between two potassium bromide pellets with a spectrometer. GC−MS was obtained using electron ionization. HRMS was obtained with a LCMS-IT-TOF mass spectrometer. UV-vis absorption spectra were obtained using Shimadzu UV-2600 spectrophotometer. Photoluminescence spectra were recorded on a Horiba Fluoromax-4 spectrofluorometer. Thin film fluorescence quantum yields were measured using a Hamamatsu absolute PL quantum yield


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spectrometer C11347 Quantaurus-QY. Fluorescence lifetimes were determined with a Hamamatsu C11367-11 Quantaurus-Tau time-resolved spectrometer. General Procedure for the Preparation of Compound 3: The reaction mixture of 2-ethynylanilines 1 (0.2 mmol), nitriles 2 (0.4 mmol), Cu(OAc)2 (10 mol %) and t-BuOK (3 equiv) were added to DMSO (0.5 mL). The mixture was stirred at 120 oC for 24 h under O2 balloon and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford substituted quinazolines 3. General Procedure for the Preparation of Compound 4: The reaction mixture of o-alkynylanilines 1 (0.2 mmol), nitriles 2 (0.4 mmol), Cu(OAc)2 (10 mol %) and t-BuOK (3 equiv) were added to toluene (0.5 mL). The mixture was stirred at 100 oC for 12 h under O2 balloon, and monitored periodically by TLC. Upon completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and filtered. The solvent was removed under vacuum. The residue was purified by flash column chromatography to afford substituted quinazolines 4. 2,4-Diphenylquinazoline (3aa)19: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 81% (45.7 mg) as a white solid: 117-119 o

C. 1H NMR (400 MHz, CDCl3, δ ppm) 8.73 (d, J = 7.3 Hz, 2H), 8.15 (dd, J = 17.4,

8.4 Hz, 2H), 7.89-7.86 (m, 3H), 7.61-7.53 (m, 7H);

13

C NMR (101 MHz, CDCl3, δ



Page 16 of 34

ppm) 168.3, 160.2, 151.9, 138.2, 137.6, 133.5, 130.5, 130.1, 129.9, 129.1, 128.6, 128.5, 126.9, 121.6. IR (KBr, cm–1): 2921, 1538, 1477, 1326, 754. HRMS (ESI) m/z: calcd for C20H15N2 [M + H]+ 283.1230; found 283.1238. 4-Phenyl-2-(p-tolyl)quinazoline

(3ab)22:

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 61% (36 mg) as a white solid: 166-168 oC. 1H NMR (400 MHz, CDCl3, δ ppm) δ 8.60 (d, J = 8.1 Hz, 2H), 8.15-8.10 (m, 2H), 7.95-7.84 (m, 3H), 7.66-7.57 (m, 3H), 7.55-7.40 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H), 13C NMR (101 MHz, CDCl3, δ ppm) δ 168.3, 160.3, 151.9, 140.8, 137.8, 135.5, 133.5, 130.2, 129.9, 129.3, 129.0, 128.7,128.5, 127.0, 126.8, 121.6, 21.5. IR (KBr, cm–1): 2919, 1533, 1456, 1334, 764. HRMS (ESI) m/z: calcd for C21H17N2 [M + H]+ 297.1386; found 297.1387. 4-Phenyl-2-(o-tolyl)quinazoline

(3ac)22:

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 57% (33.7 mg) as a white solid: 72-74 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.18 (dd, J = 8.2, 5.0 Hz, 2H), 8.03-7.97 (m, 1H), 7.95-7.83 (m, 3H), 7.6-7.55 (m, 4H), 7.38-7.31 (m, 3H), 2.69 (s, 3H), 13C NMR (101 MHz, CDCl3, δ ppm) 168.1, 163.4, 151,7, 138.8, 137.5, 137.4, 133.6, 131.3, 130.8, 130.2, 130.0, 129.2, 129.0, 128.6, 127.3, 127.0, 126.0, 121.0, 21.3. IR (KBr, cm–1): 2919, 1537, 1462, 1259, 1087, 799. HRMS (ESI) m/z: calcd for C21H17N2 [M + H]+ 297.1386; found 297.1382. 2-(4-Isopropylphenyl)-4-phenylquinazoline (3ad): Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 59% (38.2 mg) as a white solid: 92-94 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.65 (d, J = 8.3 Hz, 2H),


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8.17-8.10 (m, 2H), 7.92-7.84 (m, 3H), 7.62-7.58 (m, 3H), 7.54-7.49 (m, 1H), 7.42 (d, J = 8.3 Hz, 2H), 3.02 (septet, J = 7.5, 6.9 Hz, 1H), 1.34 (s, 3H), 1.32 (s, 3H),

13

C

NMR (101 MHz, CDCl3, δ ppm) 168.1, 160.3, 151.9, 151.5, 137.7, 135.9, 133.4, 130.1, 129.8, 129.0, 128.7, 128.4, 126.9, 126.7, 126.6, 121.5, 34.1, 23.8. IR (KBr, cm–1): 2960, 1536, 1453, 1339, 1261, 770. HRMS (ESI) m/z: calcd for C23H21N2 [M + H]+ 325.1699; found 325.1697. 2-(4-Methoxyphenyl)-4-phenylquinazoline (3ae)19: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 41% (25.6 mg) as a white solid: 158-160 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.66 (d, J = 8.8 Hz, 2H), 8.11 (t, J = 8.6 Hz, 2H), 7.93- 7.82 (m, 3H), 7.66-7.55 (m, 3H), 7.51 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H);

13

C NMR (101 MHz, CDCl3, δ ppm)

δ168.2, 161.8, 160.1, 152.1, 137.8, 133.5, 131.0, 130.0, 129.9, 128.9, 128.5, 127.0, 126.5, 121.4, 113.9, 55.4. IR (KBr, cm–1): 2920, 1533, 1461, 1337, 1251, 765. HRMS (ESI) m/z: calcd for C21H17N2O [M + H]+ 313.1335; found 313.1342. 2-(Benzo[d][1,3]dioxol-5-yl)-4-phenylquinazoline (3af)21: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 62% (40.4 mg) as a white solid: 169-170 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.32 (dd, J = 8.2, 1.6 Hz, 1H), 8.20 (d, J = 1.6 Hz, 1H), 8.09 (dd, J = 8.6, 2.8 Hz, 2H), 7.88-7.85 (m, 3H), 7.63-7.56 (m, 3H), 7.50 (ddd, J = 8.2, 7.0, 1.0 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.04 (s, 2H), 13C NMR (101 MHz, CDCl3, δ ppm) 168.1, 159.7, 152.0, 149.8, 148.1, 137.7, 133.5, 132.7, 130.2, 129.9, 129.0, 128.5, 127.0, 126.7, 123.6, 121.5, 108.9, 108.3, 101.4. IR (KBr, cm–1): 2921, 1536, 1495, 1333, 774. HRMS (ESI) m/z: calcd



Page 18 of 34

for C21H15N2O2 [M + H]+ 327.1128; found 327.1127. 2-(4-Chlorophenyl)-4-phenylquinazoline (3ag)22: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 84% (53 mg) as a white solid: 190-192 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.65 (d, J = 7.9 Hz, 2H), 8.14 (t, J = 7.5 Hz, 2H), 7.94-7.84 (m, 3H), 7.60-7.56 (m, 4H), 7.49 (d, J = 7.9 Hz, 2H),

13

C NMR (101 MHz, CDCl3, δ ppm) 168.5, 159.3, 151.9, 137.5, 136.8, 136.7,

133.7, 130.1, 130.0, 129.1, 128.7, 128.5, 127.2, 127.0, 121.7. IR (KBr, cm–1 ): 2918, 1533, 1471, 1332, 1159, 1084. HRMS (ESI) m/z: calcd for C20H14ClN2 [M + H]+ 317.0840; found 317.0843. 2-(2-Chlorophenyl)-4-phenylquinazoline (3ah)22: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 67% (42.3 mg) as a white solid: 93-95 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.19 (t, J = 7.5 Hz, 2H), 7.97-7.84 (m, 4H), 7.63-7.52 (m, 5H), 7.42-7.38 (m, 2H);

13

C NMR (101 MHz,

CDCl3, δ ppm) 168.1, 161.2, 151.4, 138.4, 137.1, 133.7, 132.9, 131.7, 130.4, 130.1, 130.0, 129.0, 128.9, 128.5, 127.9, 127.7, 126.9, 121.2. IR (KBr, cm–1): 2920, 1535, 1481, 1335, 757. HRMS (ESI) m/z: calcd for C20H13ClN2Na [M + Na]+ 339.0659; found 339.0653. 2-(4-Bromophenyl)-4-phenylquinazoline (3ai)20: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 87% (62.6 mg) as a white solid: 192-194 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.62-8.55 (m, 2H), 8.13 (dd, J = 12.2, 4.6 Hz, 2H), 7.93-7.84 (m, 3H), 7.67-7.54 (m, 6H),

13

C NMR (101

MHz, CDCl3, δ ppm) 168.5, 159.3, 151.9, 137.5, 137.1, 133.7, 131.7, 130.2, 130.1,


Page 19 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


130.0, 129.1, 128.6, 127.2, 127.0, 125.3, 121.7. IR (KBr, cm–1): 2920, 1534, 1459, 1386, 694. HRMS (ESI) m/z: calcd for C20H14BrN2 [M + H]+ 361.0335; found 361.0331. 4-Phenyl-2-(4-(trifluoromethyl)phenyl)quinazoline (3aj)20: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 88% (63 mg) as a white solid: 124-126 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.82 (d, J = 8.1 Hz, 2H), 8.15 (t, J = 8.7 Hz, 2H), 7.89 (dd, J = 8.9, 5.1 Hz, 3H), 7.78 (d, J = 8.2 Hz, 2H), 7.65 -7.54 (m, 4H),

13

C NMR (101 MHz, CDCl3, δ ppm) 168.5, 158.8,

151.9, 141.6, 137.5, 133.8, 132.1(q, J = 270.8 Hz), 130.2, 130.1, 129.3, 128.9, 128.6, 127.6, 127.1, 125.4 (q, J = 3.8 Hz), 124.0 (q, J = 270.8 Hz), 122.0,

19

F NMR (376

MHz, CDCl3, δ ppm) -62.57. IR (KBr, cm–1): 2924, 1539, 1485, 1319, 1107, 769. HRMS (ESI) m/z: calcd for C21H14F3N2 [M + H]+ 351.1104; found 351.1110. 2-(Naphthalen-2-yl)-4-phenylquinazoline (3ak)19: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 51% (33.9 mg) as a white solid: 182-184 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.26 (s, 1H), 8.83 (dd, J = 8.6, 1.3 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.3 Hz, 1H), 8.08- 8.03 (m, 1H), 8.00 (d, J = 8.7 Hz, 1H), 7.98-7.86 (m, 4H), 7.67-7.49 (m, 6H), 13C NMR (101 MHz, CDCl3, δ ppm) 168.5, 160.2, 152.0, 137.7, 135.5, 134.7, 133.7, 133.5, 130.3, 130.0, 129.4, 129.1, 129.0, 128.6, 128.2, 127.7, 127.1, 127.0, 126.1, 125.6, 121.8. IR (KBr, cm–1): 2921, 1540, 1465, 1332, 698. HRMS (ESI) m/z: calcd for C24H17N2 [M + H]+ 333.1386; found 333.1382. 2-(Naphthalen-1-yl)-4-phenylquinazoline (3al)19: Purified via flash column



Page 20 of 34

chromatography with 40% ethyl acetate/petroleum ether, yielding 64% (42.5 mg) as a white solid: 171-173 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.85 (d, J = 8.4 Hz, 1H), 8.27 (ddd, J = 27.1, 12.9, 4.5 Hz, 3H), 8.03-7.90 (m, 5H), 7.67-7.52 (m, 7H),

13

C

NMR (101 MHz, CDCl3, δ ppm) 168.4, 162.7, 151.7, 137.4, 136.5, 134.2, 133.7, 131.3, 130.1, 130.0, 129.9, 129.6, 129.1, 128.5, 128.4, 127.4, 126.9, 126.7, 126.1, 125.7, 125.3, 121.2. IR (KBr, cm–1): 2920, 1535, 1464, 1325, 768. HRMS (ESI) m/z: calcd for C24H16N2Na [M + Na]+ 355.1206; found 355.1209. 2-(Furan-2-yl)-4-phenylquinazoline

(3am)19:

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 71% (38.6 mg) as a white solid: 166-168 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.16 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.89-7.78 (m, 3H), 7.69 (s, 1H), 7.60-7.55 (m, 3H), 7.53-7.47 (m, 2H), 6.59 (dd, J = 3.4, 1.7 Hz, 1H);

13

C NMR (101 MHz, CDCl3, δ

ppm) 168.8, 153.5, 152.8, 151.6, 145.3, 137.2, 133.9, 130.1, 130.0, 128.9, 128.6, 127.1, 127.0, 121.6, 114.3, 112.2. IR (KBr, cm–1): 2922, 1536, 1481, 1336, 758. HRMS (ESI) m/z: calcd for C18H12N2NaO [M + Na]+ 295.0842; found 295.0841. 4-(4-Chlorophenyl)-2-(4-ethylphenyl)quinazoline (3bn): Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 57% (39.3 mg) as a white solid: 178-180 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.59 (d, J = 8.2 Hz, 2H), 8.15 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.91- 7.81 (m, 3H), 7.62-7.49 (m, 3H), 7.36 (d, J = 8.1 Hz, 2H), 2.75 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H),

13

C NMR (101 MHz, CDCl3, δ ppm) 167.0, 160.4, 152.1, 147.2, 136.2,

136.1, 135.6, 133.6, 131.5, 129.2, 128.8, 128.7, 128.2, 127.0, 126.6, 121.4, 28.9, 15.5.


Page 21 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


IR (KBr, cm–1): 2922, 1536, 1459, 1333, 759. HRMS (ESI) m/z: calcd for C22H18ClN2 [M + H]+ 345.1153; found 345.1155. 4-(4-Chlorophenyl)-2-(3,5-dimethylphenyl)quinazoline (3bo): Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 56% (39.1 mg) as a white solid: 185-187oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.31 (s, 2H), 8.19 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.95-7.84 (m, 3H), 7.66-7.52 (m, 3H), 7.18 (s, 1H), 2.48 (s, 6H),

13

C NMR (101 MHz, CDCl3, δ ppm) 167.1, 160.6,

152.0, 138.1, 137.9, 136.2, 136.1, 133.7, 132.5, 131.6, 129.3, 128.9, 127.1, 126.5, 126.4, 121.5, 21.5. IR (KBr, cm–1): 2921, 1540, 1479, 1340, 757. HRMS (ESI) m/z: calcd for C22H18ClN2 [M + H]+ 345.1153; found 345.1152. 4-(4-Chlorophenyl)-2-(thiophen-2-yl)quinazoline

(3bp):

Purified via flash

column chromatography with 40% ethyl acetate/petroleum ether, yielding 66% (42.5 mg) as a white solid: 157-159 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.19 (d, J = 3.5 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.60- 7.46 (m, 4H), 7.21-7.15 (m, 1H); 13C NMR (101 MHz, CDCl3, δ ppm) 167.1, 157.2, 151.9, 144.0, 136.4, 135.7, 133.9, 131.5, 130.0, 129.4, 128.9, 128.3, 126.9, 126.7, 121.3. IR (KBr, cm–1): 2921, 1531, 1483, 1338, 711. HRMS (ESI) m/z: calcd for C18H12N2SCl [M + H]+ 323.0404; found 323.0398. 2-(Furan-2-yl)-4-(p-tolyl)quinazoline

(3cm):

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 41% (23.5 mg) as a white solid: 138-140 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.16 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88-7.86 (m, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.69 (s, 1H),



Page 22 of 34

7.53-7.49 (m, 2H), 7.39 (d, J = 7.9 Hz, 2H), 6.60-6.59 (m, 1H), 2.46 (s, 3H);

13

C

NMR (101 MHz, CDCl3, δ ppm) 168.9, 153.5, 152.9, 151.6, 145.2, 140.3, 134.4, 133.8, 130.1, 129.3, 128.9, 127.3, 126.9, 121.7, 114.2, 112.2, 21.5. IR (KBr, cm–1 ): 2921, 1534, 1478, 1263, 755. HRMS (ESI) m/z: calcd for C19H14N2NaO [M + Na]+ 309.0998; found 309.1003. N,N-Dimethyl-4-(2-(4-(trifluoromethyl)phenyl)quinazolin-4-yl)aniline

(3dj):

Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 46% (36.2 mg) as a white solid: 136-138 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.82 (d, J = 8.2 Hz, 2H), 8.29 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.92-7.83 (m, 3H), 7.77 (d, J = 8.3 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 6.89 (d, J = 8.8 Hz, 2H), 3.10 (s, 6H),

13

C NMR (101 MHz, CDCl3, δ ppm) 168.1, 158.7, 152.0,

151.9, 142.0, 138.8 (q, J = 36.9 Hz), 133.3, 131.9, 129.1, 128.8, 127.5, 127.0, 125.3 (q, J = 3.6 Hz), 124.9, 124.3 (q, J = 270.4 Hz), 121.9, 111.8, 40.3,

19

F NMR (376

MHz, CDCl3, δ ppm) -62.73. IR (KBr, cm–1): 2919, 1643, 1462, 1262, 754. HRMS (ESI) m/z: calcd for C23H19F3N3 [M + H]+ 394.1526; found 394.1533. 7-Methoxy-2,4-diphenylquinazoline

(3ja):

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 57% (35.6 mg) as a white solid: 235-237 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.67 (d, J = 7.3 Hz, 2H), 8.01 (d, J = 9.2 Hz, 1H), 7.87-7.85 (m, 2H), 7.58-7.57 (m, 3H), 7.54-7.47 (m, 4H), 7.16 (d, J = 9.1 Hz, 1H), 4.03 (s, 3H);

13

C NMR (101 MHz, CDCl3, δ ppm) 167.3,

163.8, 160.9, 154.4, 138.3, 137.9, 130.5, 130.1, 129.8, 128.7, 128.5, 128.4, 120.3, 117.1, 106.6, 55.8. IR (KBr, cm–1): 2922, 1763, 1693, 1242, 1026, 697. HRMS (ESI)


Page 23 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


m/z: calcd for C21H17ON2 [M + H]+ 313.1335; found 313.1336. 6-Chloro-2,4-diphenylquinazoline

(3ka)19:

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 49% (30.9 mg) as a white solid: 195-197 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 8.71-8.66 (m, 2H), 8.14 (d, J = 9.0 Hz, 1H), 8.10 (d, J = 2.1 Hz, 1H), 7.88-7.81 (m, 3H), 7.65-7.60 (m, 3H), 7.55-7.50 (m, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 167.7, 160.5, 150.4, 137.7, 137.1, 134.6, 132.7, 130.8, 130.7, 130.3, 130.1, 128.7, 128.7, 128.6, 125.8, 122.2. IR (KBr, cm–1): 2988, 1748, 1244, 1049, 798. HRMS (ESI) m/z: calcd for C20H14ClN2 [M + H]+ 317.0840; found 317.0844. 2-Phenylquinazoline (4aa)23: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 79% (32.5 mg) as a white solid: 98-100 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.46 (s, 1H), 8.67-8.59 (m, 2H), 8.12-8.06 (m, 1H), 7.93-7.86 (m, 2H), 7.64-7.51 (m, 4H); 13C NMR (101 MHz, CDCl3, δ ppm) δ 161.1, 160.5, 150.8, 138.0, 134.1, 130.6, 128.7, 128.6, 127.3, 127.1, 123.6. IR (KBr, cm–1): 2923, 1556, 1455, 1266, 757. HRMS (ESI) m/z: calcd for C14H11N2 [M + H]+ 207.0917; found 207.0919. 2-(p-Tolyl)quinazoline (4eb)23: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 71% (31.2 mg) as a white solid: 97-99 oC. 1

H NMR (400 MHz, CDCl3, δ ppm) 9.44 (s, 1H), 8.52 (d, J = 8.2 Hz, 2H), 8.13-8.01

(m, 1H), 7.95-7.80 (m, 2H), 7.64-7.50 (m, 1H), 7.34 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H); 13

C NMR (101 MHz, CDCl3, δ ppm) 161.2, 160.4, 150.8, 140.9, 135.3, 134.1, 129.4,

128.6, 127.1, 127.0, 123.5, 21.52. IR (KBr, cm–1): 2926, 1559, 1459, 1266, 755.



Page 24 of 34

HRMS (ESI) m/z: calcd for C15H13N2 [M + H]+ 221.1073; found 221.1079. 2-(4-Fluorophenyl)quinazoline (4eq)23: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 79% (35.4 mg) as a yellow solid: 136-137 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.45 (s, 1H), 8.68- 8.58 (m, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.95-7.87 (m, 2H), 7.62 (dd, J = 11.0, 4.0 Hz, 1H), 7.24-7.13 (m, 2H);

13

C NMR (101 MHz, CDCl3, δ ppm)165.9, 163.5, 160.5, 160.1, 150.7,

134.3, 134.2, 130.70 (d, J = 8.7 Hz), 128.6, 127.22 (d, J = 14.2 Hz), 123.5, 115.5 (d, J = 21.5 Hz), 19F NMR (376 MHz, CDCl3, δ ppm) -110.52. IR (KBr, cm–1): 2921, 1585, 1402, 1219, 800. HRMS (ESI) m/z: calcd for C14H10N2F [M + H]+ 225.0823; found 225.0825. 2-(4-Chlorophenyl)quinazoline

(4eg)23:

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 82% (39.4 mg) as a yellow solid: 137-139 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.43 (s, 1H), 8.60-8.51 (m, 2H), 8.09-8.01 (m, 1H), 7.95-7.86 (m, 2H), 7.66-7.57 (m, 1H), 7.53-7.43 (m, 2H); 13

C NMR (101 MHz, CDCl3, δ ppm) 160.5, 160.0, 150.7, 136.9, 136.5, 134.3, 129.9,

128.8, 128.6, 127.5, 127.2, 123.6. IR (KBr, cm–1): 2920, 1575, 1405, 1265, 751. HRMS (ESI) m/z: calcd for C14H10ClN2 [M + H]+ 241.0527; found 241.0528. 2-(4-Bromophenyl)quinazoline (4ei)23：Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 72% (40.7 mg) as a yellow solid: 122-123 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.43 (s, 1H), 8.49 (d, J = 8.5 Hz, 2H), 8.06 (d, J = 8.8 Hz, 1H), 7.89 (dd, J = 7.9, 6.3 Hz, 2H), 7.69-7.56 (m, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 160.4, 160.2, 150.7, 137.0, 134.3, 131.8, 130.2,


Page 25 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


128.6, 127.5, 127.2, 125.4, 123.7. IR (KBr, cm–1): 2991, 1578, 1404, 1265, 752. HRMS (ESI) m/z: calcd for C14H10N2Br [M + H]+ 285.0022; found 285.0019. 2-(4-(Trifluoromethyl)phenyl)quinazoline (4ej)23: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 87% (47.7 mg) as a white solid: 144-146 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.47 (s, 1H), 8.74 (d, J = 8.2 Hz, 2H), 8.10 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.78 (d, J = 8.3 Hz, 2H), 7.68-7.61 (m, 1H),

13


141.3, 134.4, 132.3 (q, J = 32.2 Hz), 128.9, 128.8, 127.9, 127.2, 125.5 (q, J = 3.8 Hz), 123.8, 123.6 (q, J = 292.6 Hz), 19F NMR (376 MHz, CDCl3, δ ppm) -62.67. IR (KBr, cm–1): 2923, 1540, 1457, 1262, 756. HRMS (ESI) m/z: calcd for C15H10F3N2 [M + H]+ 275.0791; found 275.0777. 2-(Furan-2-yl)quinazoline (4em)23: Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 54% (21.2 mg) as a white solid: 116-118 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.36 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.89-7.85 (m, 2H), 7.68 (d, J = 0.8 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.45 (d, J = 3.4 Hz, 1H), 6.60-6.59 (m, 1H); 13C NMR (101 MHz, CDCl3, δ ppm) δ 160.7, 154.1, 152.5, 150.4, 145.4, 134.5, 128.4, 127.3, 123.4, 114.1, 112.3. IR (KBr, cm–1): 2923, 1587, 1483, 1262, 755. HRMS (ESI) m/z: calcd for C12H8N2NaO [M + Na]+ 219.0529; found 219.0526. 7-Methyl-2-(4-(trifluoromethyl)phenyl)quinazoline (4hj): Purified via flash column chromatography with 40% ethyl acetate/petroleum ether, yielding 76% (43.8 mg) as a white solid: 157-159 oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.37 (s, 1H),



Page 26 of 34

8.71 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 8.6 Hz, 1H), 7.80-7.72 (m, 3H), 7.68 (s, 1H), 2.57 (s, 3H); 13C NMR (101 MHz, CDCl3, δ ppm) 159.9, 158.9, 149.2, 147.0, 141.4, 138.1, 136.7, 131.9 (q, J = 32.0 Hz), 128.6, 128.4, 125.4 (q, J = 3.8 Hz), 124.2 (q, J = 270.5 Hz), 122.9, 21.7, 19F NMR (376 MHz, CDCl3, δ ppm) -62.66. IR (KBr, cm–1): 2921, 1635, 1415, 1266, 754. HRMS (ESI) m/z: calcd for C16H12F3N2 [M + H]+ 289.0947; found 289.0949. 2-(4-Ethylphenyl)-7-methylquinazoline

(4hn):

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 72% (35.7 mg) as a white solid: 67-69oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.35 (s, 1H), 8.51 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 8.6 Hz, 1H), 7.71-7.69 (m, 1H), 7.65 (s, 1H), 7.36 (d, J = 8.3 Hz, 2H), 2.74 (q, J = 7.6 Hz, 2H), 2.55 (s, 3H), 1.30 (t, J = 7.6 Hz, 3H);

13

C NMR

(101 MHz, CDCl3, δ ppm) 160.6, 159.7, 149.4, 146.9, 137.2, 136.3, 135.7, 128.5, 128.3, 128.1, 125.8, 123.5, 28.9, 21.6, 15.4. IR (KBr, cm–1): 2921, 1562, 1423, 1263, 754. HRMS (ESI) m/z: calcd for C17H17N2 [M + H]+ 249.1386; found 249.1385. 7-Bromo-2-(4-ethylphenyl)quinazoline

(4in):

Purified

via

flash

column

chromatography with 40% ethyl acetate/petroleum ether, yielding 69% (43 mg) as a white solid: 143-145oC. 1H NMR (400 MHz, CDCl3, δ ppm) 9.36 (s, 1H), 8.51 (d, J = 8.0 Hz, 2H), 8.05 (s, 1H), 7.94 (s, 2H), 7.36 (d, J = 7.9 Hz, 2H), 2.77-2.70 (m, 2H), 1.29 (d, J = 7.6 Hz, 3H);

13


147.6, 137.5, 135.1, 130.4, 129.2, 128.7, 128.3, 124.4, 120.5, 28.9, 15.4. IR (KBr, cm–1): 2921, 1543, 1418, 1263, 753. HRMS (ESI) m/z: calcd for C16H14BrN2 [M + H]+ 313.0335; found 313.0335.


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ASSOCIATED CONTENT Supporting Information Copies of NMR spectra for all compounds and X-ray crystallographic data for 3aa. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Authors [email protected]; [email protected] Notes The authors declare no competing financial interest. ACKNOWLEDGMENT The authors thank the National Program on Key Research Project (2016YFA0602900), the National Natural Science Foundation of China (21490572 and 21420102003), and Pearl River S&T Nova Program of Guangzhou (201610010160) for financial support. REFERENCES (1) (a) Tang, C.; Jiao, N. Copper-Catalyzed Aerobic Oxidative C-C Bond Cleavage for C-N Bond Formation: From Ketones to Amides. Angew. Chem. Int. Ed. 2014, 126, 6646-6650. (b) Shao, Y.; Zhang, F.; Zhang, J.; Zhou, X. Lanthanide-Catalyzed Reversible Alkynyl Exchange by Carbon-Carbon Single-Bond Cleavage Assisted by a Secondary Amino Group. Angew. Chem. Int. Ed. 2016, 55, 11485-11489. (c) Morioka, T.; Nishizawa, A.; Furukawa, T.; Tobisu, M.; Chatani, N. Nickel-Mediated Decarbonylation of Simple Unstrained Ketones through the Cleavage of Carbon-Carbon Bonds. J. Am. Chem. Soc. 2017, 139, 1416-1419. (d) Chen, P.-H.;



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Copper-Catalyzed Synthesis of Substituted Quinazolines from

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